The primate lentiviruses include the human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency viruses (SIVs) (Barre-Sinoussi, F., et al. (1983) Science 220:868-871; Clavel, F. (1987) AIDS 1:135-140; Daniel, M. D., et al. (1985) Science 228:1201-1204; Desrosiers, R. C. (1990) Ann. Rev. Immunol. 8: 557-578; Gallo, R. C, et al. (1984) Science 224:500-503). HIV-1 and HIV-2 infect humans, HIV-1-like viruses infect chimpanzees, and SIV variants infect African monkeys. Humans infected by HIV-1 and HIV-2 and Asian macaques infected by certain SIV strains often develop life-threatening immunodeficiency due to depletion of CD4-positive T lymphocytes (Fauci, A., et al. (1984) Ann. Int. Med. 100:91-106; Letvin, N. L., et al. (1985) Science 230:71-739, 19).
In humans, HIV infection causes Acquired Immunodeficiency Syndrome (AIDS), an incurable disease in which the body's immune system breaks down leaving the victim vulnerable to opportunistic infections, e.g., pneumonia, and certain cancers, e.g., Kaposi's Sarcoma. AIDS is a major global health problem. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that there are now over 34 million people living with HIV or AIDS worldwide, some 28.1 million of those infected individuals reside in impoverished sub-Saharan Africa. In the United States, approximately one out of every 500 people are infected with HIV or have AIDS. Since the beginning of the epidemic, AIDS has killed nearly 19 million people worldwide, including some 425,000 Americans. AIDS has replaced malaria and tuberculosis as the world's deadliest infectious disease among adults and is the fourth leading cause of death worldwide.
HIV and SIV tropism is determined by cell-type-specific and species-specific host factors. Following entry into the host cell, uncoating of the viral core, reverse transcription, nuclear access, and integration of the viral DNA into the host genome must occur to establish a permanent infection (Arts, E. J., and M. A. Wainberg. (1996) Adv. Virus Res. 46:97-163; Freed, E. O. (1998) Virology 251:1-15; Whitcomb, J. M., and S. H. Hughes. (1992) Annu. Rev. Cell. Biol. 8:275-306). Early, post-entry restrictions to retrovirus infection can determine tropism at the species level. HIV-1 encounters a post-entry block in Old World monkeys, whereas SIVmac is blocked in most New World monkey cells (Himathongkham, S., and P. A. Luciw. (1996) Virology 219:485-488; Hofmann, W., et al. (1999) J. Virol. 73:10020-10028; Shibata, R., et al. (1995) J. Gen. Virol. 76:2723-2730). These species-specific restrictions occur prior to or concurrent with reverse transcription; at most, low levels of early reverse transcripts are made in restricted cells (Cowan, S., et al. (2002) Proc. Natl. Acad. Sci. USA 99:11914-11919; Himathongkham, S., and P. A. Luciw. (1996) Virology 219:485-488; Munk, C, et al. (2002) Proc. Natl. Acad. Sci. USA 99:13843-13848; Shibata, R., et al. (1995) J. Gen. Virol. 76:2723-2730). The viral determinant of susceptibility to these blocks is the capsid protein (Cowan, S., et al. (2002) Proc. Natl. Acad. Sci. USA 99:11914-11919; Hatziioannou, T., et al. (2004) J. Virol. 78:6005-6012; Kootstra, N. A., et al. (2003) Proc. Natl. Acad. Sci. USA 200:1298-1303; Owens, C. M., et al. (2004) J. Virol. 78:5423-5437; Owens, C. M., et al. (2003) J. Virol. 77:726-731; Towers, G., et al. (2000) Proc. Natl. Acad. Sci. USA 97:12295-12299). The early restriction to HIV-1 and SIV is mediated by dominant host factors, the activity of which can be titrated by the introduction of virus-like particles containing proteolytically processed capsid proteins of the restricted viruses (Besnier, C, et al. (2002) Proc. Natl. Acad. Sci. USA 99:11920-11925; Bieniasz P. D. (2003) Trends Microbiol. 11:286-291; Cowan, S., et al. (2002) Proc. Natl. Acad. Sci. USA 99:11914-11919; Hatziioannou, T., et al. (2003) EMBO J. 22:385-394; Owens, C. M., et al. (2004) J. Virol. 78:5423-5437; Towers, G., et al. (2002) J. Virol. 76:2548-2550; Towers, G. J., et al. (2003) Nat. Med. 9:1138-1143). Thus, in the cells of specific monkey species, host restriction factors apparently interact, directly or indirectly, with the HIV-1 or SIV capsid and prevent its progression along the infectious pathway.
The identification of the factor(s) that mediate this blocking will shed light on the poorly understood series of events that govern the fate of retroviral capsids after entry, permit the development of animal models for the study of HIV-1 pathogenesis, treatment and prophylaxis, and suggest approaches to intervene in transmission or spread within the host.